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Figure 3. Thalamic lacunes associated with decreases in NAA

Figure 3. Thalamic lacunes associated with decreases in NAA

The finding in SIVD that [NAA] losses in cortical regions correlated with subcortical infarction load and WMH, implies that subcortical vascular disease is responsible for cortical changes in SIVD. There are several possible explanations for this finding. First, and most likely, is that subcortical infarctions cause functional deafferentiation of the cerebral cortex, sometimes termed subcortical-cortical diaschisis. This is consistent with PET studies showing in SIVD hypometabolism and hypoperfusion in cortical regions,® especially in the frontal lobe.(7) In support of this view, MRS studies on animals have shown trans-synaptic decrease of NAA levels following acute deafferentation without neuronal loss.(8) It is therefore conceivable that the cortical [NAA] losses in SIVD could indicate deafferented neurons in a state of functional inactivity with a possibility for recovery rather than frank neuron loss. A second explanation is that neurons are damaged or lost via transneuronal degeneration, secondary to subcortical infarctions.(9) With the assumption that [NAA] reflects neuron density, the results imply further that a secondary degeneration causes disproportionately greater loss of neuronal than to nonneuronal cells.

A third possibility is that cortical [NAA] reductions are due to cortical ischemia, with or without micro-infarctions in the cortex, undetectable with MRI. There are two arguments against this view: First, quite remarkably, we found no [NAA] reduction in white matter in SIVD (or in AD). It would seem reasonable that a widespread ischemic process, which affected cortex and caused subcortical infarctions and WMH would also produce [NAA] reduction in white matter. Second, [NAA] reductions can occure preferentially in the frontal lobe, as the comparison between subjects with and without thalamic lacunes showed. In presence of a generalized ischemic process, however, one would expect that the entire cortex is affected and not the frontal region singled out. Eventually, it will be necessary to obtain autopsy information to exclude micro-infarctions and concurrent AD as potential cause of cortical [NAA] reduction in SIVD.

2.3 Reduced Medial Temporal Lobe NAA in CIND

We have previously showed that AD patients have significantly less NAA concentration in the medial temporal lobe (MTL) and parietal lobe gray matter (GM) than cognitively normal subjects.(10) This study sought to determine whether cognitively impaired but non-demented (CIND) elderly individuals who are at risk for developing dementia exhibit a similar pattern of reduced NAA in the MTL and parietal lobe GM. In addition, we also compare regional NAA patterns and hippocampal volumes in CIND patients who remained cognitively stable with those who later became demented during follow-up (mean follow-up duration: 3.6 + 1.7 years; range: 1-7 years). Seventeen CIND patients (mean age: 75.4 ± 6.8 years), 24 AD patients (mean age: 74.8 ± 6.9 years), and 24 cognitively normal subjects (mean age: 76.0 ± 6.3 years) were studied using MRSI and MRI. There were no significant hippocampal volume differences between CIND patients and cognitively normal subjects. However, CIND subjects had 21% less MTL NAA (p = 0.005) than controls. Moreover, dichotomizing CIND patients revealed greater MTL NAA reductions in patients who later became demented than patients who remained cognitively stable during follow-up. Together, these results suggest that NAA reduction in the MTL can be detected in the absence of significant hippocampal atrophy and before the development of dementia. Thus, MTL NAA could potentially serve as an early marker for AD.


Posttraumatic stress disorder (PTSD) is characterized by exposure to markedly distressing traumatic event(s), re-experiencing symptoms, emotional numbing, and increased arousal. Biological alterations include adrenergic hyperresponsiveness (11), increased thyroid activity (12), low cortisol levels, and increased negative feedback sensitivity of the hypothalamic-pituitary-adrenal (HPA) axis following low-dose dexamethasone administration (13). In addition, magnetic resonance imaging (MRI) studies reported decreased volumes of the hippocampus in both, Vietnam combat veterans (14, 15) and noncombat trauma victims (16, 17) with PTSD. However, laterality was inconsistent across these MRI studies, with volume decreases being reported in the right, the left, and both hippocampi. In a preliminary 1H MRSI study (18), we found decreased hippocampal NAA in a small number of veterans with PTSD, many of whom had been recently abusing alcohol, compared to healthy controls without a history of alcohol abuse. Another 1H MRS study reported NAA reductions in medial temporal lobe structures of veteran PTSD subjects (19). Therefore, in a new MRSI study on a new group of PTSD

subjects we sought to determine if 1H MRSI measurements could detect NAA changes in the hippocampus of PTSD, separate from volume changes.

Eighteen male patients with combat-related PTSD (mean age 51.2 ± 2.5 years) and 19 male control subjects (mean age 51.8 ± 3.2) were studied using MRI and Proton MR spectroscopic imaging. Both groups had no alcohol and drug abuse during the past 5 years. PTSD and control subjects had similar volumes of hippocampus and entorhinal cortex. We found NAA was significantly reduced by about 23% and creatine containing compounds were reduced between 11% and 26% bilaterally in the hippocampus of PTSD when compared to control subjects (Table 1). However, there were no significant differences in hippocampal or ERC volumes between PTSD patients without recent history of alcohol abuse and control subjects. This contrasted previous reports of hippocampal atrophy in PTSD, suggesting that alcohol abuse may have been at least in part responsible for these previous findings.

Table 1. NAA reductions in PTSD patients.

Metabolites PTSD Control Differenceb Effect Size

Table 1. NAA reductions in PTSD patients.

Metabolites PTSD Control Differenceb Effect Size


2.8 ± 0.8

3.7 ± 0.8


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